Prenatal inflammation suppresses blood Th1 polarization and gene clusters related to cellular energy metabolism in preterm newborns

Abstract

Chorioamnionitis (CA, fetal membrane inflammation) predisposes to preterm birth and is associated with increased neonatal infection risk, but the separate effects of prematurity, CA, and postnatal adaptations on this risk are unclear. Using pigs as models for infants, we examined the systemic immune‐metabolic status in cesarean‐delivered preterm pigs, with and without CA induced by intra‐amniotic (IA) LPS exposure. At birth, cord blood of preterm pigs showed neutropenia and low expressions of innate and adaptive immune genes, relative to term pigs. IA LPS induced CA and fetal systemic innate immune activation via complement and neutrophil‐related pathways. These were mainly modulated via cellular regulations rather than granulopoiesis, as validated by the in vitro LPS stimulation of cord blood. After birth, IA LPS‐exposed preterm pigs did not follow normal immune‐metabolic ontogenies found in fetuses or newborns without prenatal insults, but showed consistently high levels of Treg, impaired Th1 polarization, and reduced expressions of multiple genes related to cellular oxidative phosphorylation and ribosomal activities. In conclusion, our results provide cellular and molecular evidence for CA‐induced distinct neonatal immune‐metabolic status with increased disease tolerance strategy, suggesting mechanisms for the clinical observation of elevated sepsis risks in immune‐compromised preterm infants born with CA.

Glucose supply and glycolysis inhibition shape the clinical fate of Staphylococcus epidermidis–infected preterm newborns

“…Numerous animal models of infection and sepsis have been established e.g., cecal ligation and puncture (23) and oral (24,25) or systemic bacterial challenge (26), but no rodent models can address the contributing effects of PN. The preterm pig is a unique model because it allows PN administration via umbilical catheter (27) and has multiple organ immaturities and infection susceptibility (26,(28)(29)(30), as found in preterm infants. Furthermore, systemic S. epidermidis administration to newborn preterm pigs can induce clinical and cellular responses (e.g., fever, inflammation, blood platelet and leukocyte depletion) that may progress to septic shock (acidemia and hypotension) 12-24 hours after infection, similar to sepsis caused by CONS and other bacteria in preterm infants (26).…”

Editorial: Immunity in Compromised Newborns

“…In this study, any postnatal gut influence of fetal inflammation appeared overshadowed by the immune-modulating effects of enteral feeding and microbial colonization just after birth. On the other hand, Muk et al showed that kidneys, in contrast to gut, lungs and liver (30), showed more robust and longer-term inflammatory reactions after prenatal Gram-negative infection in preterm pigs, confirming the postnatal systemic immune suppression assessed by blood transcriptome analyses (32). It remains that the immune effects of fetal inflammation are highly species-, time-, age-, pathogen-and organ-specific.…”

Parenteral glucose supply and pharmacological glycolysis inhibition determine the clinical fate of infected preterm newborns

“…In an in vitro experiment, the frequency of Treg cells in stimulated blood was analyzed as previously described(28). In brief, blood after bacterial stimulation was lyzed to remove erythrocytes, washed with PBS, permeabilized (permabilization buffer, Thermofisher), blocked with porcine serum (Thermofisher Scientific), and stained with a mixture of FITC-conjugated mouse-IgG2b anti-porcine CD4 antibody (clone MIL17), APC-conjugated rat-IgG2a anti-porcine Foxp3 antibody (clone FJK-16s), and analyzed by a BD Accuri C6 flow cytometer (BD Biosciences, USA).…”

“…Whole blood RNA of selected samples from in vitro and in vivo experiments was analyzed by whole transcriptome shotgun sequencing, as previously described(28), to profile immunometabolic pathways affected by relevant interventions. Briefly, RNA-seq libraries were constructed using 1000 ng RNA and VAHTS mRNA-seq V3 Library Prep Kit for Illumina (Vazyme, China).…”

“…The preterm pig is a unique model because it allows PN administration via umbilical catheter, similar to preterm infants (25). Further, preterm pigs mimic the immaturities of multiple organs and infection susceptibility in preterm infants (24, 26–28). Systemic S. epidermidis administration to newborn preterm pigs can induce clinical and cellular responses (fever, inflammation, immune cell depletion) progressing to septic shock (acidemia, and hypotension) 12-24h post-infection (24).…”